We have shown that adenosine has important electrophysiological effects that may impact on the genesis and therapy of a number of cardiac arrhythmias, particularly those observed during hypoxia or ischemia. This proposal represents an expansion of our continued effort to understand the cardiac effects of adenosine and its role as modulator of cardiac impulse generation and conduction. The present study has been designed to: 1) address specifically several important facets of -the negative dromotropic effect of adenosine, 2) define how, and to what extent, adenosine acts as a mediator of AV conduction disturbances during hypoxia and ischemia, 3) determine how adenosine inhibits the cardiac actions of interventions known to modify cellular cyclic AMP (cAMP) and 4) determine the effects of adenosine on triggered automaticity. Our approach is multidisciplinary (basic and clinical studies) and we will use multiple levels of experimentation, i.e., single cardiac cells, isolated AV node preparations, isolated hearts, and humans. By use of various electrophysiological and morphological techniques we will identify the different regions and cell types in the AV node and determine the precise site of adenosine action. The isolated cells and the small AV node preparation (1 mm2) are ideal for the proposed voltage clamp and kinetic studies; these studies will permit analysis of ionic currents and precise determination of the kinetics of the action of adenosine. The role of cAMP in mediating the adenosine effect on triggered automaticity and characterization of the adenosine receptor that mediates this action will be determined by measurement of cellular cAMP and the use of pharmacological probes. The importance of endogenous adenosine in AV conduction disturbances associated with hypoxia and ischemia will be examined with pharmacological modulators of the action of adenosine. In addition, tissue and plasma levels of adenosine will be measured. As a direct extension of the animal experiments, a series of clinical studies aimed at determining: 1) the electrophysiological effects of adenosine in the human myocardium, 2) the effect of adenosine in atrial and ventricular tachyarrhythmias, and 3) the possible role of adenosine in ischemic AV block. This multidisciplinary and multi-level approach should provide an integrated picture of the cardiac actions of adenosine as well as contribute to a better understanding of the etiology, diagnosis, and possible treatment of certain conduction rhythm disturbances associated with myocardial hypoxia and ischemia.